Regenerative medicine is a field in medicine that relates to the ability to correct congenital anomalies and to repair or replace tissues and organs that have been destroyed by age, disease, or trauma. To date, promising preclinical and clinical data supported the possibility of using regenerative medicine to treat both chronic diseases and acute insults, as well as maladies affecting a wide range of organ systems and contexts, such as dermal wounds, cardiovascular diseases and traumas, cancer treatments, and more. One of the regenerative medicine therapies that have been used widely is stem cells.
Stem cells, especially mesenchymal and hematopoietic stem cells, play an important role in treating chronic diseases, such as leukemia, bone marrow, autoimmune disease, and urinary problems. Despite considerable advancements in stem cell biology, their applications are limited by ethical concerns about embryonic stem cells, tumor development, and rejection. Nevertheless, many of these constraints, are being overcome, which could lead to significant advancements in disease management. This review discusses the current developments and advancements of regenerative medicine therapy (RMT) advancements in Malaysia compared to other Asian countries. The limitations in the application of RMT are also highlighted.
1. Introduction
Regenerative medicine therapy (RMT) is a process of replacing and regenerating human cell tissues and organs to restore or establish normal function. This field holds the promise of regenerating tissues and organs in the body by replacing damaged tissues or by stimulating growth mechanisms for tissue and organ healing (Mao and Mooney 2015). In RMT, tissues and organs are grown in the laboratory before they are safely implanted when the body is unable to heal (Bioengineering NIOBIA 2020). The tissues are retrieved in two ways: through cell culture and from cells that have been extracted from humans or animals (Fuchs 2012). To grow stem cells, scientists first extract samples from adult tissue or an embryo (Bioengineering NIOBIA 2020). The cells are then placed in a controlled culture where they will divide and proliferate but not specialized further. A stem-cell line is a collection of stem cells that are dividing and replicating in a controlled environment (Bioengineering NIOBIA 2020). Regenerative medicine strives to make it easier to repair or regenerate damaged tissues or organs (Bioengineering NIOBIA 2020).
A healthy human tissue, such as the liver, could naturally regenerate if destroyed either by disease or injury (Krafts 2010). Such tissue can return to its original size and function but not its original shape (Krafts 2010), however, the tissues do not regenerate in some cases (Krafts 2010). This is where regenerative medicine comes into play as it aims to promote tissue regeneration in the body or use tissue engineering for tissue replacements. As shown in Figure 1, RMT involves cell therapy, tissue engineering, and biomaterials. Biomaterials, also known as scaffolds, consist of natural and synthetic polymers. Meanwhile, common growth factors are critical molecules for tissue repair and regeneration, such as platelet, fibroblast, and vascular endothelial cells. Adult stem cells (induced pluripotent stem cells) are living cells that originate from adult somatic cells, and their potential use in personalized regenerative medicine has been demonstrated (Stoddard-Bennett and Pera 2018). These components are important because of the potential of regenerative medicine in organ and tissue repairs, such as brain, liver, skin, bone, cartilage, and nerve cell, and their applications in clinical settings.
Among the RMTs, stem cells transplantation, cellular therapy, and platelet-rich plasma (PRP) are the most prominent medical therapies being offered to patients. Others such as fibroblast cells, stem cell, and their cellular matrix, including PRP are used in anti-aging therapies. These diverse benefits depict that the potential of RMT can be further explored and implemented. Hence, this review is important to highlight and compare the progress and update of current RMT treatments or services including clinical trials in Malaysia with other developed Asian countries.
Malaysia has grown and become a strong competitor in the global health and medical tourism sector, which is now identified as a center of medicine in the region. There are two categories of health tourism offered in Malaysia: medical tourism and wellness programs. Patients may choose medical treatments and stay on the recuperating period, or they may come for a holiday and explore the various wellness programs in over 14 different states in Malaysia. With more than 35 well-established private hospitals, Malaysia offers a wide choice of state-of-the-art in-patient facilities and comfortable accommodation ranging from private rooms to luxury suites, a fine variety of meals, and highly qualified and trained nurses at a reasonable cost. Additionally, these hospitals are certified and internationally recognized quality standards, such as MS ISO 9002, and accredited by the Malaysian Society for Quality of Health.
Malaysia has become a preferred health tourism destination for many abroad patients. It offers competitive and affordable pricing and favorable exchange rate, highly qualified, experienced, and skilled consultants. Malaysia is ranked first in medical tourism compared to other countries as it attracted approximately 1.3 million medical tourists in 2019. Although the diverse culture and religion could be barriers in the implementation and practice of RMT, however, the unique entity and tolerant multi-racial and multi-cultural environment in Malaysia has successfully accommodated patients of different cultures and religions.
1.1 Stem Cell Therapies
Stem cells are repair units of the body that provide a central function in the regeneration of organ tissues. The main function of stem cells is to replenish dying cells and regenerate damaged tissues, which have the potential to be used as treatments for many diseases, such as cardiovascular diseases and different types of cancer. These events have heightened the hope of achieving stem cell-based replacement therapy in medicine. The three types of stem cells include embryonic stem cells, adult stem cells, and perinatal stem cells. For embryonic stem cells, the embryo (at this stage, called a blastocyst) is isolated from inner cell mass (ICM) that can form all the specialized tissues that make up the human body on days 3–5 following fertilization and before implantation. Embryonic stem cells were first isolated from mice’s ICM from preimplantation mouse blastocysts in vitro (Evans and Kaufman 1981; Martin 1981). These cells, termed Embryonic Stem Cells (ESCs), could self-renew indefinitely in culture, while being able to be differentiated into cells derived from all three germ layers, except for the placenta. Human embryonic stem cells (hESC) are obtained from the inner cell mass of an in vitro fertilized embryo that has been donated for research purposes after receiving informed consent. These pluripotent stem cells, which can transform into any cell type, are only found in the early developmental stages (Mehta 2014).
There are four types of adult stem cells, namely, the Hematopoietic Stem Cells (HSCs), Mesenchymal Stem Cells (MSCs), Neural Stem Cells (NSCs), and Epithelial Stem Cells (EpiSCs). ESCs are pluripotent, meaning they can produce every cell type in the fully formed body except the placenta and umbilical cord. These cells are extremely significant since they provide a sustainable resource for research into normal development and disease, as well as drug and therapy testing. Adult stem cells are assumed to be tissue-specific, with the ability to develop only into offspring cells of the tissues they originated from (Fang et al., 2004). Furthermore, adult stem cells have a limited ability to differentiate; they can be either be multipotent or unipotent. Firstly, HSCs are the rare and multipotent cells that reside in the bone marrow (BM), and they are responsible for the life-long production of all types of mature blood cells (Bryder et al., 2006). HSCs are cells that give rise to other blood cells via a process called hematopoiesis. Hematopoiesis refers to the production of all mature blood cells, and hematopoietic stem cells can undergo self-renewal and replenish all blood cell types (Seita and Weissman 2010).
HSCs containing grafts are being used in the treatment of blood cell diseases, such as leukemia and autoimmune disorders. MSCs can be found in the bone marrow and can be isolated in the tissues, including lung, cord blood, peripheral blood, and fallopian tube (Klingemann et al., 2008). This stem cell can differentiate to form adipocytes, bone cells, cartilage, muscle cells, neural cells, and skin cells. The umbilical cord tissue, molar teeth, body fat, and amniotic fluid are examples of the common sources for MSCs. Researchers have discovered the ability to augment a person’s stem cell count through transplantation with younger and more capable cells by collecting MSCs from donated cord tissue and increasing them to larger quantities (Ullah et al., 2015). MSCs are a popular source for regenerative medicine given their ability to respond to mechanical environments, including substrate mechanics and extrinsic mechanical stimuli (Steward and Kelly 2015). Perinatal stem cells are stem cells in amniotic fluid and umbilical cord, which could differentiate into specialized cells, such as adult stem cells (Zakrzewski et al., 2019). Stem cells have been widely used in RMT applications worldwide (Zakrzewski et al., 2019). Their ability to self-renew and differentiate to various cell types present an exceptional potential and possibility for RMT applications. The most common stem cell therapy widely used in RMT is HSCs transplantation (Khaddour et al., 2021). Meanwhile, bone marrow, peripheral blood, and umbilical cord blood are the most common sources of the target cells in HSCs transplantation (Hordyjewska et al., 2015).
1.2 Tissue Engineering
Tissue engineering is a biomedical engineering discipline that restores, maintains, improves, or replaces biological tissues using a combination of cells, engineering, materials technologies, and appropriate biochemical and physicochemical parameters (Bioengineering NIOBIA 2020). Tissue engineering evolved from the biomaterial field, which refers to the practice of combining scaffolds, cells, and biologically active molecules into functional tissues. Tissue engineering aims to assemble functional constructs that restore, maintain or improve damaged tissue or whole organs (Bioengineering NIOBIA 2020). There are three components of tissue engineering which are; 1) reparative cells that can form functional matrices, 2) appropriate scaffold for transplantation, 3) bio-reactive molecules that promote and choreograph the production of the desired tissue. These three components can be employed separately or in combination to regenerate organs or tissues (de Isla et al., 2010). The scaffolds are typically made up of a biodegradable polymer, extracellular matrix (ECM), and growth factors, and they serve as a skeleton for cells to fill and eventually grow into three-dimensional tissues (Kim et al., 2016). The extracellular matrix is made and secreted by groups of cells, which serves as a relay station for several signaling molecules in addition to supporting the cells (Assunção et al., 2020). Resultantly, cells receive messages from a variety of sources emerging from the immediate environment. Each signal can set off a series of events that determine the cell’s fate (Levin et al., 2017). These processes have been successfully managed by researchers to repair damaged tissues or even build new ones by studying how individual cells respond to signals, interact with their environment, and organize into tissues and organisms (de Isla et al., 2010).
In addition to the extracellular matrix, a few growth factors components exist in tissue engineering. Growth factors are important chemicals for tissue regeneration and repair (Zheng et al., 2019). As a result, recombinant growth factors have sparked extensive interest in the field of regenerative medicine. While the use of growth factors to enhance tissue healing has shown encouraging outcomes in preclinical studies, clinical success is not guaranteed. The translation of growth factors is frequently hindered by their short half-life, fast dispersion away from the delivery site, and low cost-effectiveness (Ren et al., 2020). Future growth factor-based regenerative therapy solutions may benefit from a more holistic approach to tissue regeneration, as it is now clear that the immune system plays a vital role in the regenerative process. Future efforts could profit from the introduction of growth factors and immunomodulators, or the production of multifunctional fusion proteins that could promote morphogenesis while influencing the immune system. Furthermore, most of the delivery systems discussed here are designed to improve the release and stability of growth factors at the delivery site (Julier et al., 2017; Larouche et al., 2018).
1.3 Biomaterials
Biomaterials are any materials that interact with biological systems, whether a substance, surface, or structure. Biomaterials can be found in nature or created in the lab with the use of metallic components, polymers, ceramics, and composite materials (Julier et al., 2017). Biomaterial-based medical devices are frequently used to replace or augment natural functions. A few examples include heart valves, hip replacements, and materials used in dentistry and surgery (Lam and Wu 2012). Biomaterials used to create porous scaffolds for tissue engineering can be divided into two categories based on their origins: natural and synthetic biomaterials (Lam and Wu 2012). Porous scaffolds can be made from naturally existing biomaterials that can be obtained from their natural sources (Chan and Leong 2008). These materials can be in their natural state, such as ECM from allografts and xenografts, or in the form of smaller building blocks, such as inorganic ceramics (i.e., calcium phosphates) and organic polymers (i.e., proteins, polysaccharides, lipids, and polynucleotides) among others. Natural biomaterials are often highly biocompatible, allowing cells to connect and proliferate with high viability. On the other hand, natural materials have limited physical and mechanical stability, making them unsuitable for some load-bearing applications (Chan and Leong 2008). This explains why researchers working with natural biomaterials resort to creating solutions that improve and reinforce the mechanical properties and stability of natural biomaterials. Inorganic biomaterials, such as bioglasses and organic biomaterials (i.e., synthetic polymers) are two types of synthetic biomaterials. Synthetic biomaterials are thought to have more regulated physical and mechanical properties and could be tailored for both soft and hard tissues. Biocompatibility becomes a serious concern for synthetic biomaterials as cells may have difficulty attaching to and growing on these materials (Chan and Leong 2008). Hence, a variety of techniques for altering the surface and bulk properties have been developed to increase biocompatibility (Morra and Cassinelli 2006).
Biomaterials are crucial in regenerative medicine, particularly in the replacement of injured tissues and organs, as well as the treatment of chronic diseases to restore normal body function (Mao and Mooney 2015). Maintaining the optimal environment for the cells to grow remains the main challenge of using biological products, such as cells in therapy. Therefore, biomaterials are being used to overcome these challenges. The function of biomaterials is to regulate cellular responses including cell-cell and cell-matrix interaction. It also acts as a scaffold to provide structural support for both cell adhesion and tissue development. Examples of biomaterials that can be used are metals, ceramics, plastics, glass, lung cells, and tissues. They could also be re-engineered into machined and molded parts, creating foams, fibers, and fabrics for medical products. Biomaterials applications may include hip joint replacement, heart valve transplantation, dental implants, and contact lenses (Choi 2019).
1.4 Aesthetic Applications of Regenerative Medicine Therapy
In addition to the clinical use of RMT in disease treatments, RMT is also known for its aesthetic applications. Most people know RMT to be an innovative therapy that allows the body to regenerate aging cells, tissues, and organs. Given its relative accessibility, the skin is a particularly appealing organ for the application of innovative regenerative therapies. Stem cells and PRP have piqued attention among these treatments due to their therapeutic potential in scar reduction, anti-aging, and alopecia treatment. Specifically, alopecia is a condition that occurs when the immune system attacks the hair follicles, causing hair loss in small spots that might be difficult to be visualized with an unaided eye. Aesthetic application of RMT is always associated with self-renewal and adaptability, which are two of the most important characteristics of stem cells.
Another important characteristic of stem cells is plasticity, which is the ability of adult tissue-specific stem cells to switch to new identities (Ramaswamy Reddy et al., 2018). Stem cells, when combined with anti-aging genes, can form a complex barrier that protects against the consequences of aging. Increased wear and tear on the body’s natural stem cells causes cellular damage and speeds up the aging process (Nguyen et al., 2019). Injecting “youthful” stem cells into the human body can regenerate existing cells, allowing the body to age gracefully and even reverse some aging symptoms. However, to date, there is inadequate clinical evidence that supports the use of stem cells in helping people age gracefully. One of the renowned aesthetic applications of RMT as an anti-aging treatment is for hair loss. Hair loss is caused by androgenic alopecia that may affect both men and women. Male-pattern baldness is another name for this problem in men. Hair loss is more common in men who transform testosterone into the more powerful metabolite dihydrotestosterone in hair follicle cells (DHT) (Rathnayake and Sinclair 2010). DHT binds to the androgen receptor in hair follicles, reducing cyclic AMP levels. The concentration of AMP (cAMP) in the cell slows down the metabolism of sugar in hair follicles and shortens the time it takes for hair follicles to grow by suppressing energy supply (Rathnayake and Sinclair 2010). As a result, the hair follicle gradually becomes more active as the resting phase of the hair becomes shorter and thinner.
Another RMT that has been used aesthetically is PRP. PRP therapy is the process of extracting platelets from the blood and centrifuging them to significantly higher concentrations (Dhurat and Sukesh 2014). Plasma is a clear, colorless liquid that is devoid of cells. Platelets are cells that are shaped like dinner plates, therefore their name. Like red blood cells and most white blood cells, platelets are produced in the bone marrow. Platelets are produced by megakaryocytes, which are extraordinarily massive bone marrow cells. Megakaryocytes undergo a process of fragmentation as they mature into gigantic cells, resulting in the discharge of over 1,000 platelets per megakaryocyte. The function of platelets is to help the body form a clot to stop bleeding, and they become active during the healing process. Platelets are the smallest size and lightest among the blood cells, making them easily pushed away from the flow of blood and towards the wall of the blood vessel. Messages are sent to platelets when a blood artery in the body is injured. Thereafter, platelets rush to the damaged area and form a plug (clot) to stop the bleeding. Adhesion is the process in which a substance spreads across the surface of a damaged blood vessel to halt bleeding. This is because platelets develop sticky tentacles that help them stick (adhere) to one another when they reach the injury site. Meanwhile, chemical signals are also sent out to recruit additional platelets. Aggregation is the process through which more platelets build up on the clot, resulting in the release of growth factors and the onset of the healing process. PRP therapy is 100% safe and works wonders on fine lines, wrinkles, scars, UV damage, and dull, worn-out skin, face, neck, back of hands, scalp, and other body parts. PRP secretes a variety of growth factors that play a role in skin regeneration. PRP may also stimulate the activation of fibroblasts, causing collagen and other matrix components to be synthesized, thereby renewing the skin. PRP can be used on any portion of the body that requires special attention, and it contains growth factors that aid in natural skin healing and collagen creation. These events make the skin appear younger and more radiant. This is a natural method of anti-aging as it employs bodily materials and produces gradual and non-invasive outcomes (Ganceviciene et al., 2012). Although PRP is frequently used in clinical dermatology, there is little experimental research that validates its effects on aged fibroblasts (Kim et al., 2011).
Since RMT in aesthetic applications is more attractive compared to its other potential in disease treatments, further innovations and developments specifically aiming to restore youthful features or anti-aging conditions have been attempted.
2 Benefits of Regenerative Medicine Therapy
One of the benefits of RMT is increased functionality. When the tendons and tissues on and around the joints are strengthened, the range of motion in the joints is increased, allowing them to move freely and perform daily duties again (Benjamin et al., 2008). Next is faster recovery, where growth factors utilized in regenerative medicine aid in the regenerative process of tissues and tendons (Dzobo et al., 2018). Furthermore, RMT is beneficial in the treatment of cardiovascular diseases. Cardiovascular diseases can deplete oxygen supply to the heart tissue, causing scar tissue to develop while altering blood pressure and blood flow (Mozos 2015). Due to the production of various growth factors, stem cells from adult bone marrow can develop into cell types that are required to repair blood arteries and the heart (Zakrzewski et al., 2019). There are a few benefits of stem cells (HSCs and MSCs), where HSCs can make up all types of blood cells while MSCs can generate bone, bone marrow, and adipocytes (Charbord 2010). Adult stem cells that can be found in the brain can differentiate into neuron cells and non-neuron cells (Maldonado-Soto et al., 2014). Several studies have shown that hematopoietic stem cells are widely used in clinical trials (Bryder et al., 2006; Zakrzewski et al., 2019; Kabat et al., 2020; Khaddour et al., 2021).
3 Known Regenerative Medicine Therapy Technology Around the World
Cell therapy is one of the regenerative medicine therapy technologies that have been used worldwide. There are two types of cell therapy, which are stem cell therapy and somatic cell therapy. These cell therapies can either be autologous or allogeneic. In allogeneic therapies, a donor is a different person, who is usually a close family member or relative. It could also potentially come from a genetically matched donor. On the other hand, autologous treatments involve cells isolated from the donor. For acute myeloid leukemia (AML) patients, treatment is usually with allogeneic hematopoietic stem cell transplantation (HSCT). The treatment aims to identify prognostic factors associated with poor outcomes. The survival outcomes for Malaysian AML patients treated with allogeneic HSCT were good, where the overall 10-years overall survival (OS) and disease-free survival (DFS) for the patients after allogeneic HSCT were 63 and 67%, respectively (Ganceviciene et al., 2012). This treatment should be considered the standard therapeutic approach. In addition, stem cells have also been used in dentistry to treat periodontal disease. Gene therapy is the tissue engineering method that has been performed in periodontology (Chatterjee et al., 2013). Another RMT that has been used globally is graphene. Graphene has been employed as a scaffold to mediate stem cell growth and differentiation, whereas other researchers utilized the RMT to successfully transplant MSCs and guide their development into specific cells (Bryder et al., 2006; Kabat et al., 2020; Khaddour et al., 2021).
Numerous cell therapy trials are ongoing in Europe, the United States, and other parts of the world (Blasimme and Rial-Sebbag 2013). The regulatory framework for development and compliance procedures for the production and commercialization has progressed alongside the establishment of industries. These measures were taken to provide guidance and legislation on the assessment of safety, quality, purity, potency, and efficacy of cell therapy trials based on the experience gained from conventional pharmaceuticals and blood banks. Nevertheless, since the cell is an active therapeutic agent, the regulatory framework for such products is significantly more complex compared to typical molecular medicines, where the final product differs from cell culture bioprocessing.
The European Medicines Agency (EMA) has recommended Holoclar for approval in the European Union as the first advanced therapy medicinal product (ATMP) using stem cells (EU) (Yu et al., 2018). In adults, Holoclar is a treatment for limbal stem cell deficit (LSCD) caused by physical or chemical burns to the eye (s). It is the initial treatment option for LSCD, a rare eye disease that can lead to blindness. Stem cells have the potential to serve as the repair system of the body. Limbal stem cells are found on the edge of the cornea (the clear front section of the eye) and the sclera (the white region of the eye). LSCD can be caused by the loss of these stem cells as a result of physical or chemical damage. The repair system of the body could be aided by stem cells. Specifically, the limbal stem cells are necessary for the corneal epithelium to regenerate and repair after damage.
